1. Field of the Invention
The invention relates to histone deacetylase imaging agents for positron emission tomography.
2. Description of the Related Art
Millions of people in the United States and all over the world are affected by brain disorders, heart disease and cancers. Decades of research in both industry and academia have failed in many cases to develop highly effective treatments. Modulation of epigenetic processes may be a new therapeutic approach applicable across most human diseases. Investigation of epigenetic changes, DNA methylation and post-translational modification of histone proteins, in the brain has provided new insight into the mediators of diverse central nervous system (CNS) disorders. However, visualizing human brain function is a challenge since the human brain is inaccessible and difficult to assay directly. Non-invasive imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), have been used in the clinical setting for imaging brain functions and disorders. Depending on the nature of the PET radiotracer or MRI sequence selected, these techniques can be used to probe structure, function, neurochemistry, or drug pharmacokinetics.
Numerous efforts have been made to develop noninvasive tools for imaging epigenetic modulators, for the detection and quantification of expression in vivo, which is critical to assess the efficacy of therapies targeting epigenetic mechanisms and to clarify the understanding of the mechanism of enzyme dysfunction in disease. Histone deacetylase is one of the most intensely investigated epigenetic enzymes, and recent studies have demonstrated that histone deacetylase enzymes are associated with numerous brain dysfunctions and disorders. To date, however, there are no validated techniques for the assessment of such enzymes in the human brain. PET is an excellent tool for the in vivo quantification of histone deacetylase biological processes and evaluates the pattern of histone deacetylase distribution in animals and human. A major advantage of PET technique is extraordinarily high sensitivity (10−9 to 10−12 M), and more sensitive than MRI (10−4 M). PET is also able to quantify the distribution of radiotracers in the brain in vivo and correlate in vitro measurement outcomes with invasive techniques such as autoradiography, immunohistochemistry and western immunoblotting. However, the lack of histone deacetylase PET imaging agents has hindered the use of PET to directly assess histone deacetylases in vivo.
Therefore, there exists a need for a radiotracer for imaging histone deacetylases using positron emission tomography.